Hematopoietic stem cell quiescence is maintained by compound contributions of the retinoblastoma gene family.
Individual members of the retinoblastoma (Rb) tumor suppressor gene family serve critical roles in the control of cellular proliferation and differentiation, but the extent of their contributions is masked by redundant and compensatory mechanisms. Here we employed a conditional knockout strategy to simultaneously inactivate all three members, Rb, p107, and p130, in adult hematopoietic stem cells (HSCs). Rb family triple knockout (TKO) mice develop a cell-intrinsic myeloproliferation that originates from hyperproliferative early hematopoietic progenitors and is accompanied by increased apoptosis in lymphoid progenitor populations. Loss of quiescence in the TKO HSC pool is associated with an expansion of these mutant stem cells but also with an enhanced mobilization and an impaired reconstitution potential upon transplantation. The presence of a single p107 allele is sufficient to largely rescue these defects. Thus, Rb family members collectively maintain HSC quiescence and the balance between lymphoid and myeloid cell fates in the hematopoietic system.
Viatour
Patrick
P
Department of Pediatrics, Stanford Medical School, Stanford, CA 94305, USA.
Somervaille
Tim C
TC
Venkatasubrahmanyam
Shivkumar
S
Kogan
Scott
S
McLaughlin
Margaret E
ME
Weissman
Irving L
IL
Butte
Atul J
AJ
Passegué
Emmanuelle
E
Sage
Julien
J
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics*; D049109:Cell Proliferation; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics*; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000378:metabolism; D009196:Myeloproliferative Disorders / Q000209:etiology; D020411:Oligonucleotide Array Sequence Analysis; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D050720:Retinoblastoma-Like Protein p107 / Q000235:genetics / Q000378:metabolism*; D050717:Retinoblastoma-Like Protein p130 / Q000235:genetics / Q000378:metabolism*
D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130